The goal of this project is to create a divided-pupil line-scanning fiber bundle-based confocal endoscope for imaging nuclear and cellular morphology in oral mucosa in vivo with reflectance contrast, and to test feasibility for screening oral precancers and cancers versus normal tissue in a clinical study on patients in vivo. The endoscope is based on a divided-pupil configuration that may overcome the major limitation of existing fiber bundle-based and scanned single fiber-based confocal endoscopes: strong back-reflections from the proximal and distal faces of the fiber element, which produces strong background noise in the images. Quantitative endpoints will be determined in terms of sensitivity and specificity to validate the feasibility of the technology and justify further development toward clinical utility. The motivation is to create confocal endoscopes for real-time noninvasive imaging in reflectance for detection of oral precancers in vivo and intra-operative mapping to guide surgery of head-and-neck cancers. Oral cancer is the fifth most common malignancy in the world. Visual examination is routinely performed but remains deficient in detecting early-stage precancers or potentially cancerous lesions. Biopsy and pathology are the current standard. However, routine biopsies in the oral cavity are neither desirable nor practical. Consequently, patients are often seriously late in seeking and/or receiving treatment and the survival rate is much lower when the cancer is more advanced. Confocal microscopy, as a noninvasive optical imaging modality that shows pathology-like nuclear and cellular detail, may enable early screening of precancers, while minimizing the need for biopsy, minimizing pain and minimizing expense. During head-and-neck surgery which includes the oral cavity, intra-operative mapping may be possible directly on the patient, to enable adequate and rapid examination of cancer-to-normal tissue margins and to guide accurate and complete excision during surgery, while preserving normal tissue. Preliminary results with a divided-pupil line-scanning confocal microscope demonstrate excellent imaging in reflectance of nuclear and cellular detail in the epithelium, deeper connective tissue and blood flow in the inside lip-buccal mucosa in vivo. The optical sectioning is 1.7 ?m and lateral resolution is 1 ?m, which is comparable to that of pathology. Our hypothesis is that a divided-pupil line-scanning confocal endoscope with the use of two fiber bundles, one for illumination and one for detection, may overcome the major limitation of strong back-reflections in recently developed coaxial fiber-based confocal endoscopes. The divided-pupil configuration may enable imaging in reflectance contrast. Nuclear and cellular detail in the epithelium, connective tissue and blood flow may be noninvasively visualized in the oral cavity in vivo with sufficiently high contrast for diagnostic as well as for intra-operative use. The proposed technology may have broad clinical impact with long-term applications in detection in vivo and intra-operative mapping to guide surgery of skin, cervical and breast cancers.